DE60126966T2 - TGF-BETA INHIBITORS AND METHODS - Google Patents

Abstract

A family of small peptides have been found to be inhibitory to TGF-beta activity, and preferably have the primary structure of Formula 1: <heading lvl="1">Formula I AA1-AA2-AA3-Pro-D-Glu-Ala wherein AA1 is leucine, phenylalanine, alpha-aminoisobutric acid, N-methylalanine, N-methylisoleucine, or isoleucine; AA2 is the same or a different amino acid residue as in AA1; and AA3 is alanine or N-methylalanine.

Description

FIELD OF THE INVENTION

The The present invention generally relates to agents containing the activity of TGF-β, for uses, such as. the inhibition of scar tissue in wound healing, as well especially small peptides with a strong anti-TGF-β activity, which counteract the effect of increased TGF-β activity of benefit is, as can be observed in many pathological conditions.

BACKGROUND

Increased quantities in activity of the transforming growth factor-β (TGF-β activity) are in a large number in pathological conditions involved, including, but not limited to, the following: (i) Fibrosis, scarring and adhesion while wound healing; (ii) fibrotic diseases of the lungs, liver, kidneys; (iii) atherosclerosis and arteriosclerosis; (iv) certain species of cancer, including prostate cancer, neuroendocrine tumors of the Digestive system, cervical cancer, glioblastomas and gastric cancer; (v) angiopathy, Vasculopathy, nephropathy; (vi) systemic sclerosis; (vii) viral Infection, e.g. Hepatitis C and HIV; and (viii) immunological disorders and deficiencies.

members the TGF-β family can be found e.g. the peptides that are known to be possess a number of biological activities associated with tumorigenesis (including angiogenesis) and the metastasis are related. TGF-β inhibited the proliferation of many cell types, including capillary endothelial cells and smooth muscle cells. TGF-β regulated down the integrin expression (α1β1, α2β1, αvβ3) into endothelial cell migration involved). Integrins are involved in the migration of all cells, including metastatic cells. TGF-β regulates matrix metalloproteinase expression, which both for angiogenesis as well the metastasis is needed down. TGF-β induces the plasminogen activator inhibitor, which is a proteinase cascade inhibits that for Angiogenesis and the Me tastase is required. TGF-β induced normal cells to inhibit transformed cells.

transforming Growth factor-β were originally according to her ability named to transform normal fibroblasts into cells that are too from an anchorage independent Growth were able. The effects of TGF-βs on cells are generally classified as proliferative and non-proliferative. As originally in the context of the first experiments on fibroblasts are TGF-βs bona fide Growth factors. Two important cell types involved in proliferation improved by TGF-β are osteoblasts and Schwann cells of the peripheral nervous system. In numerous cells are TGF-βs however, strong inhibitors of cell proliferation. This negative Growth control may be the regulatory mechanism that governs the Controlled regeneration of certain types of tissue, and could at play a role in the initiation of carcinogenesis.

The most important non-proliferative function of TGF-βs is the improvement the formation of extracellular Matrices. Although this is mainly through the increased Transcription of both collagen and fibronectin is achieved will wear the inhibition of the proteases from the degradation of the matrix also to their Stability at. The breakdown of extracellular Matrix is by reducing the secretion of proteases themselves and the simultaneous increase inhibited the amount of protease inhibitors.

by virtue of the large area applicability the TGF-βs in clinical therapies they were the core element of numerous Research. Although much of it the carried out Researching in vitro uses has been confirmed by recent in vivo studies some of the more promising in vitro effects.

The natural Members of the family of transforming growth factors-β are located up in one area of a molecular weight of 25 KDa.

clinical Uses of growth factors, including TGF-βs, may be due their size, the May cause immune reactions to be limited. The human TGF-β-1 is e.g. a homodimeric 25,000 dalton protein. In addition to potential adverse immunological reactions are large proteins due to the difficulties often not the best candidates for administration and delivery for medicines.

Due to the involvement of TGF-β in a large number of serious pathological conditions There is considerable interest in the development of inhibitors of TGF-β. Many of the proposals for TGF-β inhibitors involved antibodies.

The U.S. Patent No. 5,662,904 , issued September 2, 1997, inventor Ferguson et al., describes, for example, a composition for use in the treatment of wounds to inhibit the formation of scar tissue. An example of such a composition includes growth factor-neutralizing antibodies, such as antibodies to TGF-β-1, TGF-β-2 and PDGF.

The U.S. Patent No. 5,972,335 , issued October 26, 1999, inventor Ferguson et al., discloses compositions comprising at least two antibodies for use in promoting the healing of wounds or fibrotic disorders wherein the first antibody is specific for a single epitope on TGF-β. 1 and the second antibody is specific for a single epitope on TGF-β-2.

The U.S. Patent No. 6,062,460 , issued October 9, 2000, inventor Ferguson, discloses the use of a soluble betaglycan (also known as TGF-β receptor III) for the use of promoting wound healing in fibrotic disorders with reduced scarring.

The U.S. Patent No. 5,958,411 , issued September 28, 1999, inventors Logan and Baird, discloses methods for the treatment of CNS pathology by the administration of neutralizing anti-TGF-β antibodies.

Antibodies and However, receptors are great Proteins. Due to the levels of TGFβ-1 in the serum of individuals with Diseases such as Prostate cancer (these high levels of up to 35 ng / ml) very big Amounts of "neutralizing" proteins, e.g. antibodies be administered. This poses a difficult problem to solve and adverse effects are expected.

Furthermore, is the increase in the number of cells and receptors in the same relationship unlikely, while the amount of growth factor in the extracellular fluid due to secretion Increases steadily from diseased cells. Therefore, a procedure Targeting the receptor means that lower amounts of one Receptor inhibitors can be administered.

BRIEF SUMMARY OF THE INVENTION

In In one aspect of the present invention, a peptide is provided, which inhibits TGF-β activity, where the peptide is the primary structure of the formula I comprises:

FORMULA I

AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala

• wherein AA _{1 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; AA _{2 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; and AA ₃ is alanine or N-methylalanine, wherein the peptide Leu-Ile-Ala-Pro-D-Glu-Ala is excluded.

The The invention further provides a peptide containing the primary structure of the formula I comprises:

FORMULA I

AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala

• wherein AA _{1 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; AA _{2 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; and AA _{3 is} alanine or N-methylalanine with the peptide leu-Ile-Ala-Pro-D-Glu-Ala being excluded for use in a method of treating fibrosis, cancer, autoimmune disease or immunosuppression of a patient's viral infection. Preferred peptides for such use include Phe-Ile-Ala-Pro-D-Glu-Ala or Leu-Phe-Ala-Pro-D-Glu-Ala.

The The invention further provides the use of a peptide which the primary structure of the formula I comprises:

FORMULA I

AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala

• wherein AA _{1 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; AA _{2 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; and AA _{3 is} alanine or N-methylalanine, with the peptide leu-Ile-Ala-Pro-D-Glu-Ala being excluded for the manufacture of a medicament for the treatment of fibrosis, cancer, autoimmune disease or for the treatment of a viral infection with a suppressed immune response is associated with a patient.

The The invention further provides the use of a peptide which the primary structure from Leu-Ile-Ala-Pro-D-Glu-Ala for the preparation a drug for the treatment of fibrosis or for treatment a viral infection associated with a suppressed immune response, in a patient.

The C-terminal alanine may also include a blocking group and can e.g. be amidated or esterified.

There it is the TGF-β inhibitors of the present invention are small peptides, they are easy to synthesize are obtained in a highly purified form and can fast through a big one Number of modalities be delivered. The peptides of formula I can e.g. topically applied to wounds become adhesions and to prevent scarring, they can be delivered by injection be the behavior of tumors, fibrotic tissue, sites of inflammation to influence and to the behavior of cells of the immune system to modulate.

DETAILED DESCRIPTION OF THE INVENTION

in the U.S. Patent No. 5,780,436 , published on July 14, 1998, as well as in WO 00/02916 of co-pending application Serial No. 09 / 113,696, filed July 10, 1998, inventors Bhatnagar, Qian and Gough, all with like determination, the inventors describe a series of small peptides they called "cytomodulin analogs", of which one activity was the TGF-β agonist, one of which was LIAP- (D-Glu) -A. These cytomodulin analogs have been suggested to be useful as agents which promote wound healing and regeneration.

In In the present application, in the aforementioned L-I-A-P- (D-Glu) -A, the by the inventors for its activity as a TGF-β agonist, now discovered, together with other new compounds, the existence of TGF-β inhibitory activity. The inventors named them with the acronym "CITA." These CITA compounds are preferred Hexapeptides with a primary structure of the formula I:

FORMULA I

AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala

• wherein AA _{1 is} an amino acid residue selected from the group consisting of leucine, phenylalanine, α-aminoisobutyric acid (Aib), N-methylalanine (NmeA), N-methylisoleucine or isoleucine; AA _{2 is the} same or different amino acid residue as described for AA ₁ ; and AA _{3 is} alanine or N-methylalanine.

Therefore For example, the L-I-A-P- (D-Glu) -A (Leu-Ile-Ala-Pro-D-Glu-Ala) previously described by the inventors is one of the preferred CITA Formula I embodiments. Two more, particularly preferred embodiments are Phe-Ile-Ala-Pro-D-Glu-Ala and Leu-Phe-Ala-Pro-D-Glu-Ala, sometimes herein referred to as "CITA-II" and "CITA-III", respectively.

The AA ₁ and AA ₂ amino acid residues of Formula I represent large, hydrophobic side chains. Without wishing to be bound by theory, it is believed that the hydrophobic side chains of AA ₁ and AA ₂ occupy the large hydrophobic pocket in the receptor and are free move and interact with multiple sections of the bag. It is believed that the presence of the proline in the four position and the D-Glu residue in the five position limits the conformation.

The surprising, antagonistic nature of CITA peptides with their D-Glu containing amino acid residues is probably due to the inability of these peptides to form a conformational domain undergo the signaling activity required after binding to the TGF-β-1 receptor.

Even though their functional side chain groups the correct relative positions and can accept alignments, to positive interactions with the complementary functional receptor groups too enable, enable it's the conformational restrictions probably not that the required peptide-receptor complex conformational subjects. This can be partly due to the rigidity of the proline and the induced rigidity of alanine on its N-terminal side to be led back, however, since some proline and hydroxyproline peptides are agonists, the D-Glu rest the lead role.

Even though D-Glu its carbonyl oxygens at the correct positions for receptor binding its inner main chain conformational tendencies differ but strong from L-Glu; the Φ, Ψ Conformation Energy Map D-amino acid is approximately a mirror image of the corresponding L-amino acid, with the mirror plane from the upper left corner to the lower right corner.

peptides of the present invention by various suitable methods, according to the prior art are well known, preferably by means of solid-phase synthesis, manual or automated, as first developed by Merrifield and by Steward et al. in Solid Phase Peptide Synthesis (1984). By chemical synthesis, the amino acids in the predetermined sequence, beginning at the C-terminus, linked. Basic solid phase method do not require binding of the C-terminal protected α-amino acid to a suitable one soluble Resin support. amino acids for the Synthesis require the protection of the α-amino acid to ensure correct formation to ensure the peptide bond with the preceding residue (or the resin support). After completion of the condensation reaction at the carboxyl end is the α-amino protecting group removed the addition of the next one Remains to allow. Several classes of α-protecting groups were added described, see Stewart et al. in Solid Phase Peptide Synthesis (1984), wherein the acid labile, urethane-based tert-butyloxycarbonyl (Boc) in the past preferred is. Other protection groups and the associated ones chemical processes can including the base labile 9-fluorenylmethyloxycarbonyl (FMOC). Also, the reactive functional amino acid side chain groups require a block until the synthesis is complete. The complex Disposition of the functional blocking groups was combined with strategies and restrictions in terms of their use by Bodansky in Peptide Synthesis (1976) and Steward et al., Solid Phase Peptide Synthesis (1984), in a review article summarized.

The Solid phase synthesis is achieved by the binding of the described C-terminal α-protected amino acid residue initiated. The binding requires activating agents, e.g. Dicyclohexylcarbodiimide (DCC) with or without 1-hydroxybenzotriazole (HOBT), diisopropylcarbodiimide (DIIPC) or ethyldimethylaminopropylcarbodiimide (EDC). After binding of the C-terminal residue, the α-amino protecting group becomes in the case of acid labile tert-butyloxycarbonyl (Boc) groups by means of trifluoroacetic acid (25%) or more) in dichloromethane. Through a neutralization step with triethylamine (10%) in dichloromethane, the free amine (compared to the Salt). After the C-terminal residue has been added to the resin, becomes the cycle of removal of protection, neutralization and the bond repeated with intermediate washes, around the protected Extend the peptide chain. Each protected amino acid will be in excess introduced (three to five times), with equimolar ones Amounts of coupling reagent in a suitable solvent. After that completely blocked Peptide finally on the resin carrier Reagents are applied to the peptide from Cleave resin and to remove the side chain blocking groups. Anhydrous hydrogen fluoride (HF) cleaves the acid labile tert-butyloxycarbonyl (Boc) chemistry groups. Several nucleophilic scavengers, such as. Dimethylsulfide and anisole are included to reduce side reactions, especially on functional side-chain groups.

Modifications may be made to confer resistance to enzymatic degradation, such as the addition of blocking groups to both the N- and C-terminal residues. Another method of preventing degradation and premature clearance by the kidney system is the use of non-natural amino acid substitutes, such as Aib and NmeA, which may be found in either and both of the AA ₁ and AA ₂ positions.

Therapeutic compositions of this invention can be formulated depending on the effective doses required and the routes of administration used. For example, pharmaceutical compositions can be formulated where the TGF-β inhibitor is present in an amount of from 1 μg / kg to 10 mg / kg Weight of the patient is present. As a general suggestion, the pharmaceutically effective total of each administered peptide is to a large extent subject to therapeutic discretion.

The Composition embodiments as therapeutic agents are administered to the patient by any means Method administered. The compositions used in therapy of the invention are formulated in a manner and dosed, which corresponds to the good medical practice and the the clinical condition of the individual patient, the route of administration, the administration plan and other facts known to physicians draws. The "effective Amount "for the herein is therefore determined by such considerations.

These strong TGF-β-1 antagonists can in the treatment of a big one Range of disorders of benefit associated with increased levels of TGF-β-1 activity including fibrosis, cancer, autoimmune diseases and a number of viral infections that cause a suppressed immune response accompanied. Each of these different applications has preferred Procedures regarding the administration. A new set of drug delivery procedures among other things, as here, small peptides emerge to the conventional ones Supplement and extend the drug delivery process. One on September 18, 2000 in C & EN, 49-65, published review article e.g. describes alternative methods of drug delivery, such as. pulmonary (inhalation) and oral formulations as well as transdermal and Injectable sustained release formulations.

For the implementation of this Invention particularly considered are topical and systemic Administered, intravenous Administration, subcutaneous administration, intraperitoneal injection, subperiosteal injection, intratracheal administration, release from polymers or pumps, implants or release from liposomes. Suitable implants (if using an implanted device will) include e.g. Gel foam, wax or microparticle-based Implants. As just one example, microsphere delivery methods are used for the injectable delayed Release of drugs adapted, with peptides on the entire microspheres can be dispersed. The used cans should be sufficient to control circulating plasma concentrations of the active To achieve ingredients that are effective. Effective doses can come from Dose-response curves to be extrapolated from in vitro or Animal model test systems come.

Become the peptides for administration by mixing with physiologically acceptable carriers, i.e. Carrier, the for the recipients in the doses and concentrations used are not When made toxic, this usually involves combining of the peptide (s) of the invention with buffers, antioxidants, such as. ascorbic acid, Low molecular weight polypeptides (less than about 10 Residues), proteins, amino acids, Carbohydrates, including glucose or dextrins, chelating agents, such as e.g. EDTA, and other excipients. When used in therapeutic Admissions must be Components should be sterile. This is by filtration through sterile Filtration membranes (0.22 μm) easy to reach.

The Peptides can in any pharmacologically acceptable carrier be, and they can, dependent on of the desired Route of administration, together with liquid carrier in liposomes, microcapsules, Polymer or wax-based preparations and preparations with delayed release formulated or formulated into tablets, pills or capsules become.

The Peptides form pharmaceutically acceptable salts with organic and inorganic acids and can be administered in the form of salts and / or can be amidated. Examples suitable acids for the Formation of pharmaceutically acceptable salts are hydrochloric, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, succinic, tartaric, lactic, gluconic, ascorbic, maleic, benzenesulfonic, methane and ethanesulfonic acid, Hydroxymethane and hydroxyethanesulfonic acid.

salts can also with suitable pharmaceutically acceptable organic base addition salts be formed. These organic bases form a class whose Limits are easily understood by the person skilled in the art. Only for the purpose of By way of illustration, it can be said that the class mono-, di- and trialkylamines, e.g. Methylamine, dimethylamine and triethylamine, and mono-, di- or trihydroxyalkylamines, e.g. Mono, di- and triethanolamines; Amino acids, such as. Arginine and lysine; guanidine; N-methyl-glucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; Tris (hydroxymethyl) aminomethane and the like. (See, e.g., "Pharmaceutical Salts, J. Pharm. Sci. 66 (1), 1-19 (1977).)

therapeutic Formulations containing at least one of the peptides may be prepared for storage optionally with physiologically acceptable carriers, excipients or stabilizers are mixed, in the form of a lyophilised cake or aqueous Solutions. acceptable Carrier, Excipients or stabilizers are used in the recipients Dosages and concentrations not toxic upon administration and include buffers such as e.g. Phosphate, citrate and other organic acids; Antioxidants, including ascorbic acid; Low-level polypeptides Molecular weight (less than about 10 residues); Proteins, e.g. Serum albumin, gelatin or immunoglobulins.

Other Components can Glycine, glutamine, asparagine, arginine or lysine; such as Monosaccharides, disaccharides and other carbohydrates, among others Glucose, mannose or dextrins; Chelating agents, e.g. EDTA; Sugar alcohols, such as. Mannitol or sorbitol; salt-forming counterions, e.g. Sodium; and / or nonionic surfactants, e.g. TWEEN, PLURONICS or PEG.

compositions can in the form of a stable conditioner, preferably in combination with a physiological saline solution become. Compositions for systemic administration are preferred as sterile isotonic parenteral injections or infusions formulated.

therapeutic Compositions are typically used as liquid solutions or suspensions or made in solid form. Wound healing formulations include usually in normal use additives such as e.g. Binders, fillers, Carrier, Preservatives, stabilizers, emulsifiers, buffers and excipients, such as. pharmaceutically acceptable grades of mannitol, lactose, Strength, Magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the same. These compositions take the form of solutions, Suspensions, tablets, pills, capsules, sustained release formulations or powders and typically contain 1% -95% of the active ingredient, preferably 2% -70%. additional Formulations for other modes of administration, such as for topical administration, include ointments, tinctures, creams, lotions and, in some cases, Suppositories. For ointments and creams conventional binders, carriers and Excipients e.g. Polyalkylene glycols or triglycerides include.

The The following examples serve to illustrate, but not the restriction of the present invention.

EXPERIMENTAL

Inhibition of TGF-β-1 activity by CITAs: The inventors used a standardized in vitro assay for TGF-β-1 as a test for the biological activity of CITAs. The inventors' test is based on inhibiting the effect of TGF-β-1 on a test cell proliferation system. In this test, mink lung epithelial MV-1 Lu cells are exposed to TGF-β-1. This leads to the inhibition of MV-1 Lu cells, as seen in the reduced DNA synthesis. The reduction in DNA synthesis can be observed by measuring the incorporation of labeled precursors into the DNA. The incorporation of ³ H-thymidine into DNA in MV-1-Lu cells is used as a benchmark for cell proliferation. MV-1 Lu cells were exposed to two different concentrations of TGF-β-1, 5.0 nM, which reduced DNA synthesis by about 70%, and 10 nM, resulting in nearly 97% inhibition in the each of the present experiments. These levels of TGF-β-1 were based on the levels of TGF-β-1 found in normal serum and in the serum of patients with peritonitis, an inflammatory disease. The normal amount of TGF-β-1 in human serum is about 2 nM (39 pG / ml). In patients with peritonitis, the amount increases to almost 10 nM (169-216 pg / ml). The incorporation of ³ H-thymidine in the absence of TGF-β-1 served as a control. To test the anti-TGF-β-1 activity of CITAs, cells were exposed to 1 nM, 10 nM and 100 nM CITA-I, CITA-II and CITA-III in the absence and presence of 5.0 nM and Exposed to 10 nM TGF-β-1.

Details of Experimental Procedures: 10 ⁴ MV-1-Lu were plated in each well of a 12-well plate in 2.0 ml minimal medium (MEM) containing nonessential amino acids and 10% fetal bovine serum. After 24 hours, the medium was replaced with serum-free MEM, and the cells were cultured for an additional two hours before replacing the medium with serum-free MEM containing the test additives. After exposure to the test medium for 24 hours, the cells were pulsed for two hours with 0.5 μCi (methyl- ³ H) -thymidine (specific activity 60 Ci / mmol). After pulse labeling, the radioactive medium was removed and the cells were washed 1 × with 10% trichloroacetic acid (TCA), 2 × with 5% TCA, then 2 × with phosphate buffered saline containing 50 μg / ml non-radioactive thymidine. The washing solutions were observed to find that no further unbound radioactive thymidine remained. The washed cell layers were dissolved in 1 ml of 0.1 N NaOH containing 1% sodium dodecylsulfate. The radioactivity in the solution was measured in a scintillation counter and expressed as decays per minute (dpm). Each test was performed in quadruplicate and data presented as mean ± standard deviation.

effects of CITAs on DNA synthesis: CITA-I, CITA-II and CITA-III decreased the DNA synthesis at all concentrations tested by about 20% over the control group. These observations confirm that the CITAs were sent to the TGF-β-1 receptors can bind. Each of the three compounds tested returned those produced by TGF-β-1 Inhibition of DNA synthesis significantly.

inhibition of TGF-β-1 activity CITAs: CITA-I, CITA-II and CITA-III caused a reversal of inhibition DNA synthesis by TGF-β-1. All concentrations of CITAs detected DNA synthesis in MV-1 Lu cells come back, the opposite 5 nM TGF-β-1 were exposed to almost the same extent as in the CITAs alone, or 2 × the extent seen in TGF-β-1 was. All concentrations of CITA-I also demonstrated DNA synthesis in cells strongly inhibited by 10 nM TGF-β-1, which to a more than 10-fold increase in DNA synthesis in the inhibited Cells led.

Table 1 shows the inhibition of TGF-β-1 activity by CITA-I, Table 2 shows the inhibition of TGF-β-2 activity by CITA-II, and Table 3 shows the inhibition of TGF-β-1 by CITA -III.

These results confirm that CITAs are potent inhibitors of TGF-β-1 activity. It should be noted that, despite the fact that the invention has been described above together with preferred specific embodiments, the description and examples are illustrative and not to limit the scope of the invention, which is defined by the scope of the appended claims.

SEQUENCE LISTING

Claims (13)

A peptide which inhibits TGF-β activity, wherein the peptide comprises the primary structure of Formula I. FORMULA I AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala wherein AA ₁ leucine, phenylalanine, α-aminoisobutyric acid, N Methylalanine, N-methylisoleucine or isoleucine; AA _{2 is} leucine, phenylalanine, α-aminoisobutyric acid, methylalanine, N-methylisoleucine or isoleucine; and AA _{3 is} alanine or N-methylalanine, with the exception of the peptide leu-lle-Ala-Pro-D-Glu-Ala. A peptide according to claim 1 comprising Phe-Ile-Ala-Pro-D-Glu-Ala. A peptide according to claim 1 comprising Leu-Phe-Ala-Pro-D-Glu-Ala. Therapeutic composition comprising the peptide according to one of the claims 1 to 3 and a physiologically acceptable carrier. A composition according to claim 4 wherein the carrier is for the topical Application is suitable. A peptide comprising the primary structure of the formula I FORMULA I AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala wherein AA _{1 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; AA _{2 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; and AA _{3 is} alanine or N-methylalanine with the peptide leu-Ile-Ala-Pro-D-Glu-Ala being excluded for use in a method of treating fibrosis, cancer, autoimmune disease or immunosuppression of a viral infection in a patient. A peptide for use according to claim 6, wherein the Peptide Phe-Ile-Ala-Pro-D-Glu-Ala or Leu-Phe-Ala-Pro-D-Glu-Ala. Use of a peptide comprising the primary structure of Formula I. FORMULA I AA ₁ -AA ₂ -AA ₃ -Pro-D-Glu-Ala wherein AA _{1 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine ; AA _{2 is} leucine, phenylalanine, α-aminoisobutyric acid, N-methylalanine, N-methylisoleucine or isoleucine; and AA _{3 is} alanine or N-methylalanine with the peptide leu-Ile-Ala-Pro-D-Glu-Ala being excluded for the manufacture of a medicament for the treatment of fibrosis, cancer, autoimmune disease or for the treatment of a viral infection with which suppressed immune response in a patient. Use according to claim 8, wherein the medicament serves for topical application. Use according to claim 8 or 9 for the inhibition of Scar tissue in wound healing. Use of a peptide containing the primary structure by Leu-Ile-Ala-Pro-D-Glu-Ala for the manufacture of a medicament for the treatment of fibrosis or for the treatment of a viral infection that causes a suppressed immune response goes hand in hand with a patient. Use according to claim 11, wherein the medicament serves for topical application. Use according to claim 11 for the inhibition of scar tissue in wound healing.